The sequence specific recognition of double helical DNA is an essential biological process responsible for the regulation of cellular functions including transcription, replication, and cell division. The ability to design synthetic molecules that bind sequence specifically to unique sites on human DNA has major implications for the treatment of genetic, oncogenic and viral diseases. Basic research on structure-function issues such as recognition and covalent modification of DNA and RNA will be carried out. Research will focus on peptide recognition of the minor groove of double helical DNA, cleavage studies of DNA by designed metalloproteins, and the development of new affinity cleaving methods for studying RNA structure and RNA-ligand interactions. Our specific objectives during the next five years are: (1) recognition of mixed sequence DNA in the minor groove by dimeric peptide analogs, (2) studies of the oxidative cleavage of DNA in the minor groove by Ni(II)GGH(Hin 139-190), (3) design of synthetic hybrid metalloproteins for sequence specific oxidative cleavage of DNA in the minor groove, (4) a general method for mapping higher order RNA structures, (5) affinity cleavage of protein-RNA complexes.